Synthesis of N-Protected β-Aminocyclopropanedicarboxylates and Their Ring Transformation to N-Benzhydryl-3-alkoxycarbonyl-4,4-dialkyl­pyrrolidin-2-ones

Abstract

An easy and short synthesis of new N-protected β-aminocyclopropanedicarboxylates, a rather unexplored class of highly activated conformationally constrained β-amino acid derivatives, is described. Michael-induced ring closure (MIRC) of diphenylmethylidenamine to 2-bromoalkylidenemalonates leads to 3,3-dialkyl-2-(diphenylmethylidenamino)cyclopropane-1,1-dicarboxylates, the reactivity of which with hydrides was investigated, yielding 3-(alkoxycarbonyl)pyrrolidin-2-ones.

Michael-induced ring closure - rearrangement - cyclopropanes - β-amino acids - N-heterocycles

References

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<A NAME="RG04005ST-33">33</A>

General Experimental Procedure.
t-BuOH was dried by distillation over CaH₂. To a mixture of malonate 3 (10 mmol) and anhyd t-BuOH (15 mL) was added diphenylmethylidenamine (10 mmol) and Et₃N (10 mmol). The reaction mixture was stirred at reflux temperature (4a: 16 h; 4b, 4d: 85 h; 4c: 24 h). For 4c, 0.7 equiv of t-BuOK were added and the reaction mixture was stirred at reflux temperature overnight. The reaction mixture was then evaporated, diluted with dry Et₂O (40 mL), filtered and concentrated. The pure cyclopropanes 4 were obtained by flash column chromatography (neutral Al₂O₃, hexane-Et₂O, 2:1) and recrystallisation (Et₂O-hexane) for 4a; repeated flash column chromatography (basic Al₂O₃, hexane-Et₂O, 9:1) for 4b-d.

<A NAME="RG04005ST-34">34</A>

All compounds gave satisfactory analytical and spectral data.
Dimethyl 3-[(Diphenylmethylidene)amino]-2,2-dimethylcyclopropane-1,1-dicarboxylate ( 4a).
White crystals. R _f (neutral Al₂O₃, hexane-Et₂O 2:1) = 0.32. Mp 87.3-87.7 °C. ¹H NMR (270 MHz, CDCl₃): δ = 1.14 (s, 3 H), 1.56 (s, 3 H), 3.47 (s, 1 H), 3.68 (s, 3 H), 3.74 (s, 3 H), 7.22-7.59 (m, 10 H). ¹³C NMR (67.5 MHz, CDCl₃): δ = 18.5, 20.5, 34.4, 46.2, 52.2, 52.5, 55.8, 128.0, 128.35, 128.41, 128.44, 128.8, 130.0, 136.2, 139.3, 166.9, 168.5, 169.2. IR (KBr): ν = 1745, 1731, 1618 cm^-1. MS (ES, pos. mode): m/z (%) = 366 (100) [M + H⁺]. Anal. Calcd for C₂₂H₂₃NO₄: C, 72.31; N, 3.83. Found: C, 72.04; N, 3.70.
Dimethyl 3-[(Diphenylmethylidene)amino]-2,2-diethylcyclopropane-1,1-dicarboxylate ( 4b).
Viscous oil. R _f (silica gel, hexane-Et₂O, 9:1) = 0.03. ¹H NMR (300 MHz, CDCl₃): δ = 0.80 (t, J = 7.4 Hz, 3 H), 1.01 (t, J = 7.4 Hz, 3 H), 1.28-1.57 (m, 2 H), 1.95-2.19 (m, 2 H), 3.51 (s, 1 H), 3.68 (s, 3 H), 3.72 (s, 3 H), 7.25-7.64 (m, 10 H). ¹³C NMR (75 MHz, CDCl₃): δ = 9.8, 10.6, 20.3, 21.7, 44.2, 47.2, 52.1, 52.5, 55.9, 128.0, 128.3, 128.4, 128.5, 128.8, 129.9, 136.2, 139.5, 166.9, 167.0, 168.7. IR (NaCl): ν = 1732, 1622 cm^-1. MS (ES, pos. mode): m/z (%) = 394 (100) [M + H⁺]. Anal. Calcd for C₂₄H₂₇NO₄: C, 73.26; N, 3.56. Found: C, 73.02; N, 3.47.
Dimethyl 2-[(Diphenylmethylidene)amino]spi-ro[2.5]octane-1,1-dicarboxylate ( 4c).
White crystals. R _f (silica gel, hexane-Et₂O, 2:1) = 0.29. Mp 92.8-94.2 °C. ¹H NMR (270 MHz, CDCl₃): δ = 1.41-2.11 (m, 10 H), 3.50 (s, 1 H), 3.68 (s, 3 H), 3.72 (s, 3 H), 7.26-7.57 (m, 10 H). ¹³C NMR (67.5 MHz, CDCl₃): δ = 25.3, 25.5, 26.1, 28.7, 30.1, 41.2, 47.1, 52.2, 52.5, 54.9, 128.0, 128.3, 128.4, 128.5, 128.8, 129.9, 136.2, 139.5, 166.9, 168.3, 168.7. IR (KBr): ν = 1749, 1728, 1623 cm^-1. MS (ES, pos. mode): m/z (%) = 406 (100) [M + H⁺]. Anal. Calcd for C₂₅H₂₇NO₄: C, 74.05; N, 3.45. Found: C, 73.91; N, 3.41.
Diethyl 3-[(Diphenylmethylidene)amino]-2,2-dimethylcyclopropane-1,1-dicarboxylate ( 4d).
White crystals. R _f (silica gel, hexane-Et₂O, 9:1) = 0.08. Mp 56.2-58.6 °C. ¹H NMR (300 MHz, CDCl₃): δ = 1.14 (s, 3 H), 1.16 (t, J = 7.15 Hz, 3 H), 1.23 (t, J = 7.15 Hz, 3 H), 1.59 (s, 3 H), 3.46 (s, 1 H), 4.06-4.23 (m, 4 H), 7.21-7.61 (m, 10 H). ¹³C NMR (75 MHz, CDCl₃): δ = 14.1, 14.2, 18.5, 20.5, 34.2, 46.4, 55.6, 60.8, 61.3, 127.9, 128.4, 128.8, 129.9, 136.3, 139.4, 166.4, 168.1, 169.1. IR (KBr): ν = 1738, 1716, 1619 cm^-1. MS (ES, pos. mode): m/z (%) = 394 (100) [M + H⁺]. Anal. Calcd for C₂₄H₂₇NO₄: C, 73.26; N, 3.56. Found: C, 73.04; N, 3.44.

<A NAME="RG04005ST-35">35</A>

These new compounds 7 and 8 gave satisfactory analytical and spectral data. Selected characterisation data.
Dimethyl {2-Methoxy-1,1-dimethyl-2-[(diphenylmethylidene)amino]ethyl}malonate ( 7).
Viscous oil. R _f (petroleum ether-EtOAc, 4:1) = 0.24. ¹H NMR (270 MHz, CDCl₃): δ = 1.01 (s, 3 H), 1.31 (s, 3 H), 3.16 (s, 3 H), 3.50 (s, 3 H), 3.67 (s, 3 H), 3.81 (s, 1 H), 4.46 (s, 1 H), 7.16-7.19 (m, 2 H), 7.31-7.47 (m, 6 H), 7.66-7.70 (m, 2 H). ¹³C NMR (67.5 MHz, CDCl₃): δ = 20.3, 20.9, 42.7, 51.7, 51.8, 56.0, 56.6, 94.9, 128.0, 128.1, 128.2, 128.4, 129.0, 130.6, 136.4, 139.2, 168.7, 168.8, 170.8. IR (NaCl): ν = 1756, 1732, 1620 cm^-1. MS (70 eV): m/z (%) = no M⁺, 365 (60), 223 (83), 216 (72), 192 (81), 181 (44), 180 (100), 166 (57), 165 (78), 104 (39), 77 (38). Anal. Calcd for C₂₃H₂₇NO₅: C, 69.50; N, 3.52. Found: C, 69.38; N, 3.44.
Dimethyl 4,4-Dimethyl-2,2-diphenyl-2,4-dihydro-3 H -pyrrole-3,3-dicarboxylate ( 8).
White crystals. R _f (silica gel, petroleum ether-EtOAc, 7:3) = 0.22. Mp 112.6-113.6 °C. ¹H NMR (300 MHz, CDCl₃): δ = 1.27 (s, 6 H), 3.46 (s, 6 H), 7.12-7.26 (m, 6 H), 7.64 (br d, J = 7.71 Hz, 4 H), 7.71 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 23.6, 51.9, 55.7, 75.2, 89.1, 126.8, 127.4, 128.9, 143.4, 169.7, 170.8. IR (KBr): ν = 1737, 1719, 1652 cm^-1. MS (ES, pos. mode): m/z (%) = 366 (100) [M + H⁺]. Anal. Calcd for C₂₂H₂₃NO₄: C, 72.31; N, 3.83. Found: C, 72.07; N, 3.75.

<A NAME="RG04005ST-36A">36a</A> Caramella P. Huisgen R. Schmolke B. J. Am. Chem. Soc.  1974,  96:  2997 

<A NAME="RG04005ST-36B">36b</A> Caramella P. Huisgen R. Schmolke B. J. Am. Chem. Soc.  1974,  96:  2999 

<A NAME="RG04005ST-37">37</A> Dejaegher Y. Mangelinckx S. De Kimpe N. Synlett  2002,  113 

<A NAME="RG04005ST-38">38</A>

General Experimental Procedure.
To a mixture of cyclopropane 4 (0.5 mmol) and MeOH (3 mL) was added NaCNBH₃ (1.25 mmol) and HOAc (0.6 mmol). The reaction mixture was stirred at r.t. (12a: 17 h; 12b: 42 h; 12c: 4 h; 12d and 11d: 48 h). The reaction mixture was poured into aq NaOH (0.5 N, 10 mL) and extracted with CH₂Cl₂ (3 × 5 mL). After drying of the organic layer (MgSO₄), filtration and evaporation, the pure pyrrolidin-2-ones 12a-c, or the mixture of 12d and 11d was obtained. Analytically pure samples could be obtained upon recrystallisation (Et₂O-hexane) for 12a; flash column chromatography (silica gel, petroleum ether-EtOAc, 4:1) for 12b,c; flash column chromatography (silica gel, hexane-Et₂O, 4:1) for 12d and 11d.

<A NAME="RG04005ST-39">39</A>

All compounds gave satisfactory analytical and spectral data.
Methyl 1-Benzhydryl-4,4-dimethyl-2-oxopyrrolidine-3-carboxylate ( 12a).
White crystals. Mp 83.3-83.7 °C. ¹H NMR (270 MHz, CDCl₃): δ = 1.04 (s, 3 H), 1.11 (s, 3 H), 2.82 (d, J = 9.6 Hz, 1 H), 3.15 (s, 1 H), 3.23 (d, J = 9.6 Hz, 1 H), 3.72 (s, 3 H), 6.65 (s, 1 H), 7.21-7.35 (m, 10 H). ¹³C NMR (67.5 MHz, CDCl₃): δ = 22.6, 28.6, 36.8, 52.0, 56.1, 58.8, 60.8, 127.4, 127.6, 128.3, 128.4, 128.5, 128.8, 138.0, 138.5, 169.4, 170.3. IR (KBr): ν = 1749, 1694 cm^-1. MS (ES, pos. mode): m/z (%) = 338 (100) [M + H⁺], 167 (9). Anal. Calcd for C₂₁H₂₃NO₃: C, 74.75; N, 4.15. Found: C, 74.36; N, 4.14.
Methyl 1-Benzhydryl-4,4-diethyl-2-oxopyrrolidine-3-carboxylate ( 12b).
Viscous oil. R _f (silica gel, petroleum ether-EtOAc, 4:1) = 0.18. ¹H NMR (300 MHz CDCl₃): δ = 0.68 (t, J = 7.4 Hz, 3 H), 0.76 (t, J = 7.4 Hz, 3 H), 1.26-1.56 (m, 4 H), 2.87 (d, J = 10 Hz, 1 H), 3.23 (d, J = 10 Hz, 1 H), 3.25 (s, 1 H), 3.73 (s, 3 H), 6.64 (s, 1 H), 7.22-7.49 (m, 10 H). ¹³C NMR (75 MHz, CDCl₃): δ = 7.6, 8.1, 24.8, 28.3, 43.4, 52.0, 53.0, 58.9, 59.1, 127.4, 127.8, 128.2, 128.4, 128.6, 129.1, 138.0, 138.6, 169.7, 170.6. IR (NaCl): ν = 1734, 1694 cm^-1. MS (ES, pos. mode): m/z (%) = 366 (100) [M +H⁺], 167 (52). Anal. Calcd for C₂₃H₂₇NO₃: C, 75.59; N, 3.83. Found: C, 75.34; N, 3.78.
Methyl 2-Benzhydryl-3-oxo-2-azaspiro[4.5]decane-4-carboxylate ( 12c).
Viscous oil. R _f (silica gel, petroleum ether-EtOAc, 4:1) = 0.17. ¹H NMR (300 MHz, CDCl₃): δ = 1.11-1.57 (m, 10 H), 2.98 (d, J = 10 Hz, 1 H), 3.21 (d, J = 10 Hz, 1 H), 3.24 (s, 1 H), 3.72 (s, 3 H), 6.65 (s, 1 H), 7.15-7.44 (m, 10 H). ¹³C NMR (75 MHz, CDCl₃): δ = 22.0, 22.5, 25.4, 32.1, 36.3, 40.7, 52.0, 53.1, 58.8, 60.2, 127.4, 127.7, 128.4, 128.5, 128.8, 138.1, 138.7, 169.4, 170.5. IR (NaCl): ν = 1736, 1694 cm^-1. MS (ES, pos. mode): m/z (%) = 378 (100) [M + H⁺], 167 (35). Anal. Calcd for C₂₄H₂₇NO₃: C, 76.36; N, 3.71. Found: C, 76.05; N, 3.61.
Ethyl 1-Benzhydryl-4,4-dimethyl-2-oxopyrrolidine-3-carboxylate ( 12d).
White crystals. R _f (silica gel, hexane-Et₂O, 4:1) = 0.27. Mp 94.9-96.1 °C. ¹H NMR (300 MHz, CDCl₃): δ = 1.06 (s, 3 H), 1.12 (s, 3 H), 1.26 (t, J = 7.15 Hz, 3 H), 2.81 (d, J = 9.63 Hz, 1 H), 3.12 (s, 1 H), 3.24 (d, J = 9.63 Hz, 1 H), 4.20 (q, J = 7.15 Hz, 2 H), 6.65 (s, 1 H), 7.21-7.38 (m, 10 H). ¹³C NMR (75 MHz, CDCl₃): δ = 14.2, 22.6, 28.8, 36.9, 56.2, 58.9, 61.0, 61.2, 127.5, 127.8, 128.4, 128.6, 128.8, 138.1, 138.7, 169.0, 170.5. IR (KBr): ν = 1737, 1683 cm^-1.
MS (ES, pos. mode): m/z (%) = 352 (100) [M + H⁺]. Anal. Calcd for C₂₂H₂₅NO₃: C, 75.19; N, 3.99. Found: C, 74.98; N, 3.93.
Diethyl [2-(Benzhydrylamino)-1,1-dimethylethyl]malon-ate ( 11d).
Viscous oil. R _f (silica gel, hexane-Et₂O, 1:1) = 0.23. ¹H NMR (300 MHz, CDCl₃): δ = 1.11 (s, 6 H), 1.22 (t, J = 7.15 Hz, 6 H), 1.63 (br s, 1 H), 2.53 (s, 2 H), 3.69 (s, 1 H), 4.14 (q, J = 7.15 Hz, 4 H), 4.72 (s, 1 H), 7.17-7.37 (m, 10 H). ¹³C NMR (75 MHz, CDCl₃): δ = 14.1, 24.0, 37.5, 57.4, 57.6, 60.9, 67.8, 126.9, 127.4, 128.4, 144.2, 168.7. IR (NaCl): ν = 3351, 1755, 1732 cm^-1. MS (ES, pos. mode): m/z (%) = 398 (100) [M + H⁺]. Anal. Calcd for C₂₄H₃₁NO₄: C, 72.52; N, 3.52. Found: C, 72.28; N, 3.43.

<A NAME="RG04005ST-40">40</A> Luche JL. J. Am. Chem. Soc.  1978,  100:  2226